Invasion

Question 1

Steps of tumour progression?

Answer 1

1. Homeostasis
2. Genetic alterations
3. Hyper-proliferation
4. De-differentiation
   • Disassembly of cell-to-cell contacts
   • Loss of cell polarity
5. Invasion
   • Increased motility
   • Cleavage of ECM proteins

Question 2

What are the 2 types of migration?

Answer 2

Individual cell migration

Collective cell migration

Question 3

Types of Individual cell migration?

Answer 3

Amoeboid - e.g. lymphomas

Mesenchymal (single) - e.g. fibrosarcoma

Question 4

Types of collective cell migration?

Answer 4

Mesenchymal (chains) - e.g. fibrosarcoma

Cluster/cohorts - e.g. epithelial cancers

Multicellular strands/sheets - e.g. epithelial cancers
• collective cell migration requires more coordination to metastasise and so still has some cell-to-cell junctions

Question 5

Describe tumour cell metastasis

Answer 5

Mimics morphogenetic events

• e.g. branching morphogenesis in the mammary glands
• e.g. migration of 1o glial cells to repair a scratch wound
• the cells STOP migrating when contact is made
• conversely, tumour cells will have NO clear migration front & no sense of direction

Question 6

EGF and genes?

Answer 6

Administration of EGF can UPREGULATE genes involved in:
• cytoskeleton regulation
• motility machinery

Question 7

What stimuli can cause a cell to move?

Answer 7

Organogenesis & morphogenesis

Wounding

GF/Chemosttractants

De-differentiation (tumours)

Question 8

What tells a cell where to go when it moves?

Answer 8

Polarity (directionality)

Question 9

What tells a cell to stop moving when it begins to move?

Answer 9

Contact-inhibition motility

Question 10

How can a cell move?

Answer 10

Specialised structures
• focal adhesion
• lamellae
• filopodium

Question 11

How is cell movement regulated?

Answer 11

The cells attach to the ECM via. INTEGRINS

Question 12

What structures does the cell use for motility and explain this

Answer 12

Filopodia
• finger-like projections rich in actin filaments
• a bundle of parallel filaments

Lamellipodia
• sheet-like protrusions rich in actin filaments
• branched & crosslinked filaments

Question 13

Why is control needed in cell movement?

Answer 13

Needed for/to:

• Coordinate happenings inside the cell itself
• Regulate adhesion/release of cell-ECM
• To respond to external influences (sensors & directionality)

Question 14

How are the cell structures for motility used to allow for motility?

Answer 14

Contraction of Filopodia and Lamellipodia can break old adhesions
• allowing the cell to maintain a motion
• a signal to move could be a nutrient source and the filaments can rapidly disassemble and then reassemble at a new site to move the cell

Actin filaments have a polarity
• there is a plus and minus end on which different proteins can bind
• Depending on the proteins that bind, the actin filaments can carry out different functions

Question 15

What are the 4 broad mechanism actin goes through to allow for motility?

Answer 15

1. Nucleation
2. Elongation
3. Capping
4. Severing
5. Cross-linking & bundling
6. Branching
7. Gel-Sol Transition (by actin severing)

Question 16

Explain the (1) stage of actin which allow for motility

Answer 16

Nucleation

Attachment of the actin to the cell inner membrane
• ARP proteins form a complex and bind to actin monomers to create a nucleated actin filament (ARPs bind to the minus end)
• This is the limiting step in actin dynamics (formation of trimers to initiate polymerisation)

Question 17

Explain the (2) stage of actin which allows for motility

Answer 17

Profilin
• facilitates actin monomer binding to the actin filament

Thymosin
• reduces actin monomer binding by sequestering the free monomers so they are not available to bind to the actin filament

Question 18

Explain the (3) stage of actin which allows for motility

Answer 18

Capping

Addition of a capping molecule (to + or – end) to limit elongation
• +-end caps – Cap Z, Gelsolin, Fragmin/Severin.
• minus-end caps – Tropomodulin, Arp complex.

Question 19

Explain the (4) stage of actin which allows for motility

Answer 19

Severing

Breaking up actin filaments:
• unsevered actin filaments grow/shrink slowly
• severed populations grow/shrink more rapidly
- proteins – gelsolin, ADF/cofilin, fragmin/severin

Question 20

Explain the (5) stage of actin which allows for motility

Answer 20

Crosslinking & Bundling

This produces differing arrangements of actin filaments.

Proteins involved include:
	alpha-actinin.
	Fimbrin.
	Filamin.
	Spectrin.
	Villin.
	Vinculin.

Question 21

Explain the (6) stage of actin which allows for motility

Answer 21

Branching

This protein enables branches of actin to come off at 70degree angles
• protein – Arp complex

Question 22

Explain the (7) stage of actin which allows for motility

Answer 22

Gel-sol transition by actin filament severing

Gels are rigid and have NOT been severed
• Sols are not rigid (i.e. can flow) and HAVE been severed.

Question 23

Signalling mechanisms that regulate the actin cytoskeleton?

Answer 23

1. Ion-flux changes
   • i.e. intracellular calcium
2. Phosphoinositide signalling
   • i.e. phospholipid binding
3. Kinases/phosphatases
   • i.e. phosphorylation of cytoskeletal proteins
4. Signalling cascades via small GTPases

Question 24

Explain how small GTPases help regulate the cytoskeleton via. the signalling pathways

Answer 24

Rho, Rac, Cdc42 sub-families belongs to the Ras super-family.
• Cdc42 –> Filopodia production
• Rac –> Lamellipodia production
• Rho –> stress fibre production

These proteins are activated by:
• receptor tyrosine kinase
• adhesion receptors
• signal transduction pathways

(onenote!!)